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DRUG DESIGN AND
THALIDOMIDE
PHARMACOLOGY
Dr Trudie Binder
Department of Pharmacology
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History of Pharmacology
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The age of Herbs, potions and
Magic
• Ancient civilizations around the world have
used plant extracts as medicines.
• Many of these are merely placeboes but
some ancient remedies are truly effective.
– Willow bark; opium
In many cultures the administration of
remedies was accompanied by magic or
religious rituals.
An appreciation that natural products themselves
had the power to cure began to emerge.
Many poisonous mixtures were made.
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The birth of modern Science and
Pharmacology.
• The 16th and 17th centuries were notable for the simultaneous
development of physiology, chemistry and physics.
• Physiologists documented the way in which the body functioned
and chemists began to develop the technologies which permitted
extractions, purification, and the synthesis of chemical substances
from plants.
• These trends began to merge as the discipline of Pharmacology:
the study of the actions of drugs or chemical substances on
physiological processes.
The term Pharmacology was first used in 1692
and is derived from the Greek ‘pharmakon’
meaning medicine
First Professor in Pharmacology was appointed in
1847 at the Imperial Russian University in Dorp;
Estonia.
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What is a drug?
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What is a drug?
An agent that interacts with specific target molecules in the body
and produces a physiological effect
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Drugs have side effects
• “Medicine sometimes grants health,
sometimes destroys it…..” Ovid, Tristia
• “If you want to explain any poison
properly, what then isn’t a poison? All
things are poison; nothing is without
poison; the dose alone causes a thing
NOT to be a poison.” (Parcelsus; 1493 –
1541 AD)
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Side effects
• Because: receptors for a drug occur in
several tissue, not just the target
tissue.
• Because: of non specificity/selectivity
of drugs.
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Salix sp: Willow Bark
Willow bark has been used throughout
the centuries in China and Europe to
reduce fever and inflammation.
In 1829 Scientists discovered that
salicin was the active principal
constituent. This led to the synthesis of
salicylic acid and acetyl salicylic acid
[Asprin].
New uses for Aspirin
continue to be found:
Cardioprotective: anticoagulant.
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Papaver Somniferum
• The Opium poppy is an
annual herb native to
Southeastern Europe and
Western Asia.
• Around the 8th Century
Arab traders brought
opium to India and China.
• In 1806, Friedrich
Serturner isolated a pure
constituent of opium hat
he named morphine.
• The main clinical use for
opioids such as
morphine is in the
treatment of pain.
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Digitalis Purpurea
• The purple foxglove is native
to most of Europe.
• From the leaves of this plant
the cardiac glycosides
digitoxin and digoxin were
isolated. These drugs are still
used to treat heart failure.
• The leaves flowers and seeds
of Digitalis are all poisonous
and can be fatal if eaten.
• At the right dosage the
digitalis toxin can cause
the heart to beat more
strongly preventing heart
failure.
Symptoms of Digitalis poisoning include a
low pulse rate, nausea, vomiting, cardiac
arrest and finally death.
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Atropa belladonna
Deadly nightshade is
native to Europe, North
Africa and West Asia.
Is considered a toxic
plant. Symptoms of
poisoning include:
dilated pupils,
tachycardia,
hallucinations, blurred
vision, loss of balance,
confusion and paralysis.
Contains Atropine, the prototype for all anticholinergic drugs and is a
competitive inhibitor of Ach.
Clinical uses include as an antidote to poisoning by anticholinesterases.
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The ‘Dark Side’
• The advances of the 19th Century did not come without a
price.
• Active constituents were more potent then the parent
compound they were derived from, but they also
demonstrated more serious side effects.
• No clinical trials were conducted and no tests on toxicity,
drug addiction and tolerance. Scientists often tested new
drugs on themselves.
– Sigmund Freud tested the effects of Cocaine on himself
– Friedrich Serturner tested morphine on himself
• At the end of the 19th Century, drugs could be bought
without prescription;
– Heroin could legally be purchased in grocery shops.
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Regulations
• Until the 1930’s drugs did not need to be tested for safety
or effectiveness.
• ‘Elixir of Sulfonamide Tragedy’ of 1937 led to the
requirement that drugs be tested for safety before they
reached the market. – 107 children died.
Establishment of the Food, Drug and
Cosmetic Act of 1938 in the USA; requiring
details of a drug’s uses and proof of its
safety.
Clinical trials were not required.
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Thalidomide
• Thalidomide was
introduced onto the
European market as a safe
sedative/hypnotic in the
late 1950’s.
• Many pregnant women
took it for morning
sickness.
• Tested on male rats only;
no teratogen testing.
• Thalidomide was found
to be a teratogen which
causes birth defects.
All drugs capable of crossing the placenta
are capable of affecting the foetus.
‘Life’ article on thalidomide “In
Britian an armless baby’s play”
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Critical exposure periods for thalidomide during human development.
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Kim J H , and Scialli A R Toxicol. Sci. 2011;122:1-6
Linking Birth Defects to Thalidomide
• 1961, the Australian Dr William McBride and the
German Dr Widukind Lenz separately linked the use
of thalidomide in early pregnancy to birth defects.
‘In recent months I have observed that the incidence
of multiple severe abnormalities in babies delivered
of women who were given the drug thalidomide
(‘Distival’) during pregnancy, as an anti-emetic or as
a sedative, to be almost 20%.’
WG McBride, The Lancet, Dec 1961
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Withdrawal of thalidomide
• Thalidomide was withdrawn in Australia,
Germany and the UK by the end of 1961.
• Eight months after the withdrawal of
thalidomide, babies stopped being born with
the characteristic limb defects.
• About 40% of babies damaged by the
effects of thalidomide died in their first year.
• There are adults alive today who are living
with disabilities caused by thalidomide.
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Mechanism of action of Thalidomide
• Mechanism of action not fully understood
• Thalidomide possesses immunomodulatory,
anti-inflammatory and anti-angiogenic
properties.
• May be related to suppression of excessive
TNF-α production and down-modulation of
selected cell surface adhesion molecules
involved in leukocyte migration.
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Mechanism of teratogenic effects??
• More than 30 hypotheses have been
proposed to explain how thalidomide
causes limb defects
• Including disruption of molecular
pathways including DNA intercalation,
acetylation of macromolecules,
interference of glutamate metabolism
and folic acid antagonism.
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New Uses for Thalidomide
• Used for the treatment of leprosy and
multiple myeloma
• Thalidomide administration to these patients
is useful in suppressing these conditions.
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1. THALOMID thalidomide 200mg hard capsule blister pack
Product
Specific Indications
MULTIPLE MYELOMA - Thalomid in combination with melphalan and
prednisone is indicated for the treatment of patients with untreated
multiple myeloma aged 65 years and over or ineligible for high dose
chemotherapy.
Thalomide, as monotherapy, is indicated for the treatment of multiple
myeloma after failure of standard therapies.
ERYTHEMA NODOSUM LEPROSUM (ENL)Thalomid is indicated for the acute treatment of the cutaneous
manifestations of moderate to severe erythema nodosum leprosum
(ENL).
Thalomid is also indicated as maintenance therapy for prevention and
suppression of the cutaneous manifestations of ENL recurrence.
Thalomid is prescribed and dispensed through the Thalidomide Risk
Management Programme
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Therapeutic goods administration
Consumer Medicine Information warning for thalidomide
Severe life-threatening birth defects:
Thalidomide has caused severe birth defects when taken
during pregnancy. Thalidomide should never be used by
women who are pregnant or who could become pregnant
whilst taking the drug or could become pregnant within 4
weeks after stopping the drug. Even a single dose can
cause severe birth defects.
Product Information warning for thalidomide
Teratogenic effects:
Thalidomide has caused severe birth defects when taken during
pregnancy. Thalidomide should never be used by women who are
pregnant or who could become pregnant whilst taking the drug or
could become pregnant within 4 weeks after stopping the drug.
Even a single dose can cause birth defects.
TGA: Fifty years of independent expert advice on prescription medicines
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Continued use of Thalidomide
1. Prescribers must educate patients on
the potential benefits and side-effects
of thalidomide
2. Patients must receive contraceptive
counselling and regular pregnancy
testing
3. Patients must provide informed
consent
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Further Regulations
• New Regulations required proof of quality, safety and
efficacy or effectiveness.
• The Australian government established:
– The Australian Drug Evaluation Committee [ADEC]:
1962
– Registry of adverse drug reactions: 1962
– Adverse Drug reactions Advisory Committee
[ADRC]:1971
• It now takes many years of research before a new drug can
be registered.
– Adverse drug reactions still occur e.g. Rofecoxib (viox)
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The Drug Design & Development Process
Target Selection
Target
Validation
Lead
Identification
Lead
Optimisation
Preclinical
Development
Clinical
Development
Drug Design & Development Jargon
Target: what the drug works on (e.g. receptor, enzyme, DNA,
channel)
Lead: a molecule that has potential to be a drug after further
modification
Pre-clinical: testing done in the test tube or in animals to determine
safety/ toxicity
Clinical: testing in humans to determine (i) safety and (ii) if the drug
works
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Rang 2006 “Drug Discovery and Development”
The Drug Design & Development Process
Changes Over Time
<1980
Target Selection
Serendipity
Insights
from pathophysiology
Lead
Identification
Lead
Optimisation
1990
Defined molecular
targets
Genomics &
other “omics”
Screening of
100-1000
compounds
at a time
Virtual screening
of vast libraries
of compounds
Testing 1-10
compounds at a time
Compounds synthesized
one at a time
Trial and error
2000
Combinatorial chemistry
Synthesis of 100-1000
compounds at a time
Computational prediction27
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Is the twenty-first century the era of
personalised medicine?
Up to 80% of potential drugs fail clinical testing.
They might actually succeed if tested only on subpopulations of patients
known (from genetic testing) to be susceptible to the benefits and not
susceptible to the side effects of the drug.
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http://www.nigms.nih.gov/About/Budget/Statements/February25_1999.htm